Heart failure and atherosclerosis share the underlying mechanisms of chronic inflammation followed by fibrosis. A highly conserved microRNA (miR), miR-33, is considered as a potential therapeutic ...target for atherosclerosis because it regulates lipid metabolism and inflammation. However, the role of miR-33 in heart failure remains to be elucidated.
To clarify the role of miR-33 involved in heart failure.
We first investigated the expression levels of miR-33a/b in human cardiac tissue samples with dilated cardiomyopathy. Increased expression of miR-33a was associated with improving hemodynamic parameters. To clarify the role of miR-33 in remodeling hearts, we investigated the responses to pressure overload by transverse aortic constriction in miR-33-deficient (knockout KO) mice. When mice were subjected to transverse aortic constriction, miR-33 expression levels were significantly upregulated in wild-type left ventricles. There was no difference in hypertrophic responses between wild-type and miR-33KO hearts, whereas cardiac fibrosis was ameliorated in miR-33KO hearts compared with wild-type hearts. Despite the ameliorated cardiac fibrosis, miR-33KO mice showed impaired systolic function after transverse aortic constriction. We also found that cardiac fibroblasts were mainly responsible for miR-33 expression in the heart. Deficiency of miR-33 impaired cardiac fibroblast proliferation, which was considered to be caused by altered lipid raft cholesterol content. Moreover, cardiac fibroblast-specific miR-33-deficient mice also showed decreased cardiac fibrosis induced by transverse aortic constriction as systemic miR-33KO mice.
Our results demonstrate that miR-33 is involved in cardiac remodeling, and it preserves lipid raft cholesterol content in fibroblasts and maintains adaptive fibrotic responses in the remodeling heart.
Despite its recommendation by the current guidelines, the role of long-term oral beta-blocker therapy has never been evaluated by randomized trials in uncomplicated ST-segment elevation myocardial ...infarction (STEMI) patients without heart failure, left ventricular dysfunction or ventricular arrhythmia who underwent primary percutaneous coronary intervention (PCI).
In a multi-center, open-label, randomized controlled trial, STEMI patients with successful primary PCI within 24 hours from the onset and with left ventricular ejection fraction (LVEF) ≥40% were randomly assigned in a 1-to-1 fashion either to the carvedilol group or to the no beta-blocker group within 7 days after primary PCI. The primary endpoint is a composite of all-cause death, myocardial infarction, hospitalization for heart failure, and hospitalization for acute coronary syndrome. Between August 2010 and May 2014, 801 patients were randomly assigned to the carvedilol group (N = 399) or the no beta-blocker group (N = 402) at 67 centers in Japan. The carvedilol dose was up-titrated from 3.4±2.1 mg at baseline to 6.3±4.3 mg at 1-year. During median follow-up of 3.9 years with 96.4% follow-up, the cumulative 3-year incidences of both the primary endpoint and any coronary revascularization were not significantly different between the carvedilol and no beta-blocker groups (6.8% and 7.9%, P = 0.20, and 20.3% and 17.7%, P = 0.65, respectively). There also was no significant difference in LVEF at 1-year between the 2 groups (60.9±8.4% and 59.6±8.8%, P = 0.06).
Long-term carvedilol therapy added on the contemporary evidence-based medications did not seem beneficial in selected STEMI patients treated with primary PCI.
CAPITAL-RCT (Carvedilol Post-Intervention Long-Term Administration in Large-scale Randomized Controlled Trial) ClinicalTrials.gov.number, NCT 01155635.
Background:The effect of body weight (BW) on bleeding and ischemic events has not been adequately evaluated in real-world percutaneous coronary intervention (PCI) practice.Methods and Results:12,690 ...consecutive patients undergoing first PCI in the CREDO-Kyoto registry cohort-2 were divided into 3 groups according to tertiles of BW stratified by sex (male; Tertile 1 <60.0 kg, 2 60.0–68.0 kg, and 3 >68.0 kg, and female; Tertile 1 <47.9 kg, 2 47.9–55.8 kg, and 3 >55.8 kg). Cumulative 5-year incidences of the primary bleeding (GUSTO moderate/severe) and ischemic (myocardial infarction/ischemic stroke) endpoints increased incrementally with decrease in BW in both strata (male Tertiles 1, 2, and 3: 13.7%, 10.3%, and 8.0%, P<0.001, and 13.9%, 11.3%, and 10.2%, P<0.001; female Tertiles 1, 2, and 3: 17.9%, 12.9%, and 10.1%, P<0.001, and 17.9%, 12.9%, and 10.1%, P<0.001). Compared with Tertile 3, the adjusted risks of Tertile 1 for the primary bleeding and ischemic endpoints remained significant in the female stratum (hazard ratio (HR): 1.45, 95% confidence interval (CI): 1.14–1.87, P=0.003, and HR:1.49, 95% CI:1.13–1.95, P=0.004), but not in the male stratum (HR:1.10, 95% CI:0.92–1.32, P=0.31, and HR:1.06, 95% CI:0.90–1.27, P=0.47).Conclusions:Cumulative incidences of bleeding and ischemic events increased incrementally as BW decreased in both men and women. The adjusted risks of underweight relative to overweight for bleeding and ischemic events were significant only in women.
Background: Polypharmacy was reported to be associated with major bleeding in various populations. However, there are no data on polypharmacy and its association with bleeding in patients undergoing ...percutaneous coronary intervention (PCI).Methods and Results: Among 12,291 patients in the CREDO-Kyoto PCI Registry Cohort-3, we evaluated the number of medications at discharge and compared major bleeding, defined as Bleeding Academic Research Consortium Type 3 or 5 bleeding, across tertiles (T1–3) of the number of medications. The median number of medications was 6, and 88.0% of patients were on ≥5 medications. The cumulative 5-year incidence of major bleeding increased incrementally with increasing number of medications (T1 ≤5 medications 12.5%, T2 6–7 16.5%, and T3 ≥8 20.4%; log-rank P<0.001). After adjusting for confounders, the risks for major bleeding of T2 (hazard ratio HR 1.21; 95% confidence interval CI 1.08–1.36; P=0.001) and T3 (HR 1.27; 95% CI 1.12–1.45; P<0.001) relative to T1 remained significant. The adjusted risks of T2 and T3 relative to T1 were not significant for a composite of myocardial infarction or ischemic stroke (HR 0.95 95% CI 0.83–1.09; P=0.47 and HR 1.06 95% CI 0.91–1.23; P=0.48, respectively).Conclusions: In a real-world population of patients undergoing PCI, approximately 90% were on ≥5 medications. Increasing number of medications was associated with a higher adjusted risk for major bleeding, but not ischemic events.
There is a scarcity of data on ischemic and bleeding events in patients who experienced major bleeding after percutaneous coronary intervention (PCI). Moreover, there also is a shortage of data on ...comparative outcomes between patients with and without interruption of an antithrombotic drug after major bleeding. We evaluated the incidence and prognostic impacts of ischemic (myocardial infarction or ischemic stroke) and bleeding (Bleeding Academic Research Consortium type 3 or 5) events after major bleeding in 12,691 consecutive patients who underwent first PCI in the Coronary Revascularization Demonstrating Outcome Study in Kyoto PCI registry cohort-3. In the entire cohort, incidence of the first ischemic event and bleeding event was 2.3 per 100 person-years and 3.8 per 100 person-years, respectively. Major bleeding (Bleeding Academic Research Consortium type 3) occurred in 2,142 patients during a median follow-up of 5.7 years. In patients with major bleeding, cumulative 30-day, 1-year, and 5-year incidence of an ischemic event was 2.6%, 4.8%, and 13.2% (3.2 per 100 person-years), respectively, whereas that of a bleeding event was 6.3%, 16.1%, and 29.2% (8.5 per 100 person-years), respectively. Ischemic and bleeding events were independently associated with mortality (hazard ratio 2.36, 95% confidence interval 1.87 to 2.96, p <0.001, and hazard ratio 2.85, 95% confidence interval 2.42 to 3.37, p <0.001). The cumulative 180-day incidence of ischemic and bleeding events was not significantly different between patients with and without interruption of an antithrombotic drug in patients with major bleeding. In conclusion, the incidence of an ischemic event after the first major bleeding was approximately 1/3 of that of recurrent major bleeding, and the rates of ischemic and bleeding events after the first major bleeding were higher than the rates of first events in the general PCI population. Both ischemic events and bleeding events were strongly associated with subsequent mortality. The incidence of ischemic and recurrent bleeding events was not different between patients with and without interruption of an antithrombotic drug.
Background Peripheral venous pressure (PVP) has been shown to be a reliable surrogate for right atrial pressure in assessing congestion in patients with heart failure (HF). Liver fibrosis markers and ...scores can be useful in assessing organ injury in patients with acute HF. This study aimed to investigate the association of liver fibrosis markers and scores with PVP in patients with acute HF. Methods and Results The 7S domain of the collagen type IV N-terminal propeptide (P4NP 7S), aspartate aminotransferase-to-platelet ratio index, fibrosis-4, and nonalcoholic fatty liver disease fibrosis score were determined along with PVP measurements before discharge in 229 patients with acute HF. The strongest correlation with PVP was found for P4NP 7S (Pearson
=0.40). Patients with high P4NP 7S levels (≥median 6.2 ng/mL) had an increased risk of cardiovascular death or HF hospitalization (adjusted hazard ratio HR, 1.80 95% CI, 1.09-3.04,
=0.02). The concomitant high PVP (≥mean 8 mm Hg)/high P4NP 7S group, in contrast to the high PVP/low P4NP 7S or low PVP/high P4NP 7S group, had a significant risk relative to the low PVP/low P4NP 7S group for cardiovascular death or HF hospitalization (adjusted HR, 2.63 95% CI, 1.43-5.05,
=0.002). A sustained elevation in PVP for 1 month postdischarge was associated with a persistent increase in P4NP 7S. Conclusions The study demonstrated the relationship between the liver fibrosis marker P4NP 7S and congestion. PVP and P4NP 7S could be useful for assessing congestion-related organ injury and predicting prognosis in patients with acute HF.
•In Japan, the median length of heart failure hospitalization was 16 days.•Of hospitalized patients, 85% were discharged with complete decongestion.•Admission and discharge Composite Congestion Score ...(CCS) correlated with outcomes.•Admission CCS correlated with postdischarge outcomes even when the CCS was 0 at discharge.
Congestion is a leading cause of hospitalization and a major therapeutic target in patients with heart failure (HF). Clinical practice in Japan is characterized by a long hospital stay, which facilitates more extensive decongestion during hospitalization. We herein examined the time course and prognostic impact of clinical congestion in a large contemporary Japanese cohort of HF.
Peripheral edema, jugular venous pressure, and orthopnea were graded on a standardized 4-point scale (0–3) in 3787 hospitalized patients in a Japanese cohort of HF. Composite Congestion Scores (CCS) on admission and at discharge were calculated by summing individual scores. The primary outcome was a composite of all-cause death or HF hospitalization. The median admission CCS was 4 (interquartile range, 3–6). Overall, 255 patients died during the median hospitalization length of 16 days, and 1395 died or were hospitalized for HF over a median postdischarge follow-up of 396 days. The cumulative 1-year incidence of the primary outcome increased at higher tertiles of congestion on admission (32.5%, 39.3%, and 41.0% in the mild CCS ≤3, moderate CCS = 4 or 5, and severe CCS ≥6 congestion groups, respectively, log-rank P < .001). The adjusted hazard ratios of moderate and severe congestion relative to mild congestion were 1.205 (95% confidence interval CI, 1.065–1.365; P = .003) and 1.247 (95% CI, 1.103–1.410; P < .001), respectively. Among 3445 patients discharged alive, 85% had CCS of 0 (complete decongestion) and 15% had a CCS of 1 or more (residual congestion) at discharge. Although residual congestion predicted a risk of postdischarge death or HF hospitalization (adjusted hazard ratio, 1.314 1.145–1.509; P < .001), the admission CCS correlated with the risk of postdischarge death or HF hospitalization, even in the complete decongestion group. No correlation was observed for postdischarge death or HF hospitalization between residual congestion at discharge and admission CCS (P for the interaction = .316).
In total, 85% of patients were discharged with complete decongestion in Japanese clinical practice. Clinical congestion, on admission and at discharge, was of prognostic value. The severity of congestion on admission was predictive of adverse outcomes, even in the absence of residual congestion.
https://clinicaltrials.gov/ct2/show/NCT02334891 (NCT02334891) https://upload.umin.ac.jp/cgi–open–bin/ctr_e/ctr_view.cgi?recptno=R000017241 (UMIN000015238)
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Background It remains controversial whether long-term clinical impact of newly diagnosed atrial fibrillation (AF) in the acute phase of acute myocardial infarction (AMI) is different from that of ...prior AF diagnosed before the onset of AMI. Methods and Results The current study population from the CREDO-Kyoto AMI (Coronary Revascularization Demonstrating Outcome Study in Kyoto Acute Myocardial Infarction) Registry Wave-2 consisted of 6228 patients with AMI who underwent percutaneous coronary intervention. The baseline characteristics and long-term clinical outcomes were compared according to AF status (newly diagnosed AF: N=489 7.9%, prior AF: N=589 9.5%, and no AF: N=5150 82.7%). Median follow-up duration was 5.5 years. Patients with newly diagnosed AF and prior AF had similar baseline characteristics with higher risk profile than those with no AF including older age and more comorbidities. The cumulative 5-year incidence of all-cause death was higher in newly diagnosed AF and prior AF than no AF (38.8%, 40.7%, and 18.7%,
<0.001). The adjusted hazard ratios (HRs) for mortality of newly diagnosed AF and prior AF relative to no AF remained significant with similar magnitude (HR, 1.31; 95% CI, 1.12-1.54;
<0.001, and HR, 1.32; 95% CI, 1.14-1.52;
<0.001, respectively). The cumulative 5-year incidence of stroke decreased in the order of newly diagnosed AF, prior AF and no AF (15.5%, 12.9%, and 6.3%, respectively,
<0.001). The higher adjusted HRs of both newly diagnosed AF and prior AF relative to no AF were significant for stroke, with a greater risk of newly diagnosed AF than that of prior AF (HR, 2.05; 95% CI, 1.56-2.69;
<0.001, and HR, 1.33; 95% CI, 1.00-1.78;
=0.048, respectively). The higher stroke risk of newly diagnosed AF compared with prior AF was largely driven by the greater risk within 30 days. The higher adjusted HRs of newly diagnosed AF and prior AF relative to no AF were significant for heart failure hospitalization (HR, 1.73; 95% CI, 1.35-2.22;
<0.001, and HR, 2.23; 95% CI, 1.82-2.74;
<0.001, respectively) and major bleeding (HR, 1.46; 95% CI, 1.23-1.73;
<0.001, and HR, 1.36; 95% CI, 1.15-1.60;
<0.001, respectively). Conclusions Newly diagnosed AF in AMI had risks for mortality, heart failure hospitalization, and major bleeding higher than no AF, and comparable to prior AF. The risk of newly diagnosed AF for stroke might be higher than that of prior AF.
Biomarkers for detection of transient myocardial ischemia in patients with unstable angina (UA) or for very early diagnosis of acute myocardial infarction (AMI) are not currently available.
We ...performed two sequential screenings of autoantibodies elevated shortly after the onset of acute coronary syndrome (ACS), and focused on metalloendopeptidase nardilysin (NRDC) among 19 identified candidate antigens. In a retrospective analysis among 93 ACS and 117 non-ACS patients, the serum level of NRDC was significantly increased in patients with ACS compared with that in patients with non-ACS (2073.5±189.8pg/ml versus 775.7±63.4pg/ml, P<0.0001). The area under the curve of NRDC for the diagnosis of ACS was 0.822 by the receiver operating characteristic curves analysis. In the time course analysis in 43 consecutive ACS patients (AMI: N=35 and UA: N=8), serum concentration of NRDC was significantly increased even in UA patients with a peak serum NRDC levels reached at admission both in AMI and UA patients. In a mouse model of AMI, we found an acute increase in serum NRDC and reduced NRDC expression in ischemic regions shortly after coronary artery ligation. NRDC expression was also reduced in infarcted regions in human autopsy samples from AMI patients. Moreover, the short treatment of primary culture of rat cardiomyocytes with H2O2 or A23187 induced NRDC secretion without cell toxicity.
NRDC is a promising biomarker for the early detection of ACS, even in UA patients without elevation of necrosis markers.
Background:Data evaluating the effects of acute coronary syndrome (ACS) relative to stable coronary artery disease (CAD) on bleeding risk after percutaneous coronary intervention (PCI) are ...scarce.Methods and Results:From the CREDO-Kyoto Registry Cohort-3, 13,258 patients undergoing first PCI (5,521 ACS; 7,737 stable CAD) were identified. Patients were further stratified according to ACS presentation and Academic Research Consortium High Bleeding Risk (HBR): ACS/HBR: n=2,502; ACS/no-HBR: n=3,019; stable CAD/HBR: n=3,905; and stable CAD/no-HBR: n=3,832. The primary bleeding endpoint was Bleeding Academic Research Consortium 3/5 bleeding, whereas the primary ischemic endpoint was myocardial infarction (MI)/ischemic stroke. Compared with stable CAD, ACS was associated with a significantly higher adjusted risk for bleeding (hazard ratio HR 1.85; 95% confidence interval CI 1.68–2.03; P<0.0001), with a markedly higher risk within 30 days (HR 4.24; 95% CI 3.56–5.06; P<0.0001). Compared with the stable CAD/no-HBR group, the ACS/HBR, no-ACS/HBR, and ACS/no-HBR groups were associated with significantly higher adjusted risks for bleeding, with HRs of 3.05 (95% CI 2.64–3.54; P<0.0001), 1.89 (95% CI 1.66–2.15; P<0.0001), and 1.69 (95% CI 1.45–1.98; P<0.0001), respectively. There was no excess adjusted risk of the ACS relative to stable CAD group for MI/ischemic stroke (HR 1.07; 95% CI 0.94–1.22; P=0.33).Conclusions:Bleeding risk after PCI depended on both ACS presentation and HBR, with a significant effect of ACS within 30 days.
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